ネオ・セルフ生成における免疫プロテアソームの機能的および病理的意義の解明

2019 Fiscal Year Annual Research Report

• Project Area: Creation, function and structure of neo-self
• Project/Area Number: 19H04813
• Research Institution: Wakayama Medical University
• Principal Investigator: 改正 恒康 和歌山県立医科大学, 先端医学研究所, 教授 (60224325)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 自己炎症性疾患 / プロテアソーム / 樹状細胞 / 血球分化

Outline of Annual Research Achievements

本研究では、自己炎症性疾患の一つであるプロテアソーム関連自己炎症症候群（PRAAS）様の症状を示す患者で認められた、免疫プロテアソームのサブユニットβ1iのアミノ酸置換をきたすde novoの新規のヘテロ遺伝子変異（β1iX）を有するマウスの解析を進めている。このβ1iXヘテロ変異マウスでは、β1iタンパクの成熟不全と共に、免疫プロテアソーム活性の軽度の障害が認められた。免疫学的には、B細胞、T細胞の減少と共に、樹状細胞の減少も認められたが、一方、好中球と単球は骨髄および脾臓において増加していた。樹状細胞、好中球、単球はいずれも造血幹細胞を起源とし、様々な前駆細胞を経て分化する。そこでこの分化過程を詳細に解析したところ、造血幹細胞に近い未熟な分化段階から、好中球、単球への分化能を保持している前駆細胞では、細胞数が増加していたが、好中球、単球への分化能がなく樹状細胞への分化能を保持している樹状細胞前駆細胞では数が若干減少していた。この結果から、β1iXヘテロ変異により、造血幹細胞から好中球、単球への分化過程が亢進している一方で、樹状細胞前駆細胞の段階で分化あるいは増殖の障害が生じていることが明かになった。今後、異常が認められた細胞種について、その細胞種自身の異常なのか、その細胞種と相互作用する、他の細胞種の異常なのか明らかにすると共に、遺伝子やタンパク質の発現パターンなどを解析することにより、その異常がどのような分子機構の破綻によって生じているのか、解明を進める。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

ヘテロ変異マウス、ホモ変異マウスにおいて認められた多彩な免疫異常について、異常が認められる分化段階の解明が順調に進んでいる。

Strategy for Future Research Activity

異常が認められた細胞において、遺伝子やタンパク質の発現を網羅的に解析し、プロテアソーム機能異常によって変動する分子群を同定すると共に、その破綻した分子基盤を明らかにする。

Research Products

• [Int'l Joint Research] Yale Univ./Harvard Medical School/Emory Univ.(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Yale Univ./Harvard Medical School/Emory Univ.
  • # of Other Institutions: 31
• [Int'l Joint Research] Univ.of Melbourne/Australian National Univ./Telethon Kids Institute(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: Univ.of Melbourne/Australian National Univ./Telethon Kids Institute
  • # of Other Institutions: 1
• [Int'l Joint Research] Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hospital Cologne(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Mainz Univ./Univ. Hospital Wuerzburg/Univ. Hospital Cologne
  • # of Other Institutions: 11
• [Int'l Joint Research] London Research Institute/Imperial College/Cardiff Univ.(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: London Research Institute/Imperial College/Cardiff Univ.
  • # of Other Institutions: 1
• [Int'l Joint Research] San Raffaele Scientific Institute/ICGEB(イタリア)
  • Country Name: ITALY
  • Counterpart Institution: San Raffaele Scientific Institute/ICGEB
• [Journal Article] Osteoprotegerin-dependent M-cell self-regulation balances gut infection and immunity. (2020)
  • Author(s): S. Kimura, Y. Nakamura, N. Kobayashi, K. Shiroguchi, E. Kawakami, M. Mutoh, H. Iwanaga, T. Yamada, M. Hisamoto, M. Nakamura, N. Udagawa, S. Sato, T. Kaisho, T. Iwanaga, K. Hase.
  • Journal Title: Nat Commun. Volume: 11 Pages: 234
  • DOI: 10.1038/s41467-019-13883-y
  • Peer Reviewed / Open Access
• [Journal Article] Microfold Cell-Dependent Antigen Transport Alleviates Infectious Colitis by Inducing Antigen-Specific Cellular Immunity. (2020)
  • Author(s): Y. Nakamura, H. Mimura, J. Kunisawa, Y. Furusawa, D. Takahashi, Y. Fujimura, T. Kaisho, H. Kiyono, K. Hase.
  • Journal Title: Mucosal Immunology Volume: Epub Pages: Epub
  • DOI: 10.1038/s41385-020-0263-0
  • Peer Reviewed / Open Access
• [Journal Article] Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade. (2020)
  • Author(s): Y. Mizumoto, H. Hemmi, M. Katsuda, M. Miyazawa, Y. Kitahata, A. Miyamoto, M. Nakamori, T. Ojima, K. Matsuda, M. Nakamura, K. Hayata, Y. Fukuda-Ohta, M. Sugiyama, T. Ohta, T. Orimo, S. Okura, I. Sasaki, K. Tamada, H. Yamaue, T. Kaisho.
  • Journal Title: Br J Cancer Volume: 122 Pages: 1185-1193
  • DOI: 10.1038/s41416-020-0757-2.
  • Peer Reviewed / Open Access
• [Journal Article] The mechanism of action of Spi-B in the transcriptional activation of the interferon-α4 gene. (2020)
  • Author(s): R. Miyazaki, H. Saiga, T. Kato, T. Bakoshi, R. Senba, A. Shintani, M. Suzuki, K. Takao, I. Sasaki, A. Iizuka, M. Sugiyama, N. Iwami, Y. Fukuda-Ohta, H. Hemmi, T. Tanaka, M. Miyake, T. Kaisho, K. Hoshino.
  • Journal Title: Biochem Biophys Res Commun Volume: 30;525 Pages: 477-482
  • DOI: 10.1016/j.bbrc.2020.02.101.
  • Peer Reviewed / Open Access
• [Journal Article] IL-12 From Endogenous cDC1, and Not Vaccine DC, Is Required for Th1 Induction. (2020)
  • Author(s): D. Ashour, P. Arampatzi, V. Pavlovic, K. U Forstner, T. Kaisho, A. Beilhack, F. Erhard, M. B Lutz.
  • Journal Title: JCI Insight Volume: 21;5 Pages: 135143
  • DOI: 10.1172/jci.insight.135143.
  • Peer Reviewed / Open Access
• [Journal Article] A defined commensal consortium induces CD8 T cells and anti-cancer immunity. (2019)
  • Author(s): T. Tanoue, et al. 全著者28名中15番目
  • Journal Title: Nature Volume: 565 Pages: 600-605
  • DOI: 10.1038/s41586-019-0878-z
  • Peer Reviewed / Open Access
• [Journal Article] Cholera toxin B induces interleukine-1β production from resident peritoneal macrophages through pyrin as well as NLRP3 inflammasome. (2019)
  • Author(s): T. Orimo, I. Sasaki, H. Hemmi, T. Ozasa, Y. Fukuda-Ohta, T. Ohta, M. Morinaka, M. Kitauchi, T. Yamaguchi, Y. Sato, T. Tanaka, K. Hoshino, K. I. Katayama, S. Fukuda, K. Miyake, M. Yamamoto, T. Satoh, K. Furukawa, E. Kuroda, K. J. Ishii, K. Takeda, T. Kaisho.
  • Journal Title: Int Immunol Volume: 31 Pages: 657-668
  • DOI: 10.1093/intimm/dxz004
  • Peer Reviewed / Open Access
• [Journal Article] Hyperglycemia is associated with psoriatic inflammation in both humans and mice. (2019)
  • Author(s): K. Ikumi, M. Odanaka, H. Shime, M. Imai, S. Osaga, O. Taguchi, E. Nishida, H. Hemmi, T. Kaisho, A. Morita, S. Yamazaki.
  • Journal Title: J Invest Dermatol Volume: 139 Pages: 1329-1338.e7
  • DOI: 10.1016/j.jid.2019.01.029
  • Peer Reviewed / Open Access
• [Journal Article] Sox8 is essential for M-cell maturation to accelerate IgA response at the early stage after weaning in mice. (2019)
  • Author(s): S. Kimura, N. Kobayashi, Y. Nakamura, T. Kanaya, D. Takahashi, R. Fujiki, M. Mutoh, Y. Obata, T. Iwanaga, T. Nakagawa, N. Kato, S. Sato, T. Kaisho, H. Ohno, K. Hase.
  • Journal Title: J Exp Med Volume: 216 Pages: 831-846
  • DOI: 10.1084/jem.20181604
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel CCDC22 mutation in a patient with severe Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia. (2019)
  • Author(s): Y. Yamashita, A. Nishikawa, Y. Iwahashi, M. Fujimoto, I. Sasaki, H. Mishima, A. Kinoshita, H. Hemmi, N. Kanazawa, K. Ohshima, K.-i. Imadome. S.-i. Murata, K.-i. Yoshiura, T. Kaisho, T. Sonoki, S. Tamura.
  • Journal Title: Int J Hematol Volume: 109 Pages: 744-750
  • DOI: 10.1007/s12185-019-02595-0
  • Peer Reviewed / Open Access
• [Journal Article] Programmed cell death ligand 1 disruption by clustered regularly interspaced short palindromic repeats/Cas9-genome editing promotes antitumor immunity and suppresses ovarian cacer progression. (2019)
  • Author(s): T. Yahata, M. Mizoguchi, A. Kimura, T. Orimo, S. Toujima, Y. Kuninaka, M. Nosaka, Y. Ishida, I. Sasaki, Y. Fukuda-Ohta, H. Hemmi, N. Iwahashi, T. Noguchi, T. Kaisho, T. Kondo, K. Ino.
  • Journal Title: Cancer Sci. Volume: 110 Pages: 1279-1292
  • DOI: 10.1111/cas.13958.
  • Peer Reviewed / Open Access
• [Journal Article] Systems analysis reveals complex biological processes during virus infection fate decisions. (2019)
  • Author(s): Argilaguet. J, Pedragosa. M, Esteve-Codina. A, Riera. G, Vidal. E, Peligero-Cruz. C, Casella. V, Andreu. D, Kaisho. T, Bocharov. G, Ludewig. B, Heath. S, Meyerhans. A.
  • Journal Title: Genome Res Volume: 29 Pages: 907-919
  • DOI: 10.1101/gr.241372.118
  • Peer Reviewed / Open Access
• [Journal Article] Type I interferon delivery by iPSC-derived myeloid cells elicits antitumor immunity via XCR1+ dendritic cells. (2019)
  • Author(s): N. Tsuchiya, R. Zhang, T. Iwama, N. Ueda, T. Liu, M. Tatsumi, Y. Sasaki, R. Shimoda, Y. Osako, Y. Sawada, Y. Kubo, A. Miyashita, S. Fukushima, Z. Cheng, R. Nakaki, K. Takubo, S. Okada, S. Kaneko, H. Ihn, T. Kaisho, Y. Nishimura, S. Senju, I. Endo, T. Nakatsura, Y. Uemura.
  • Journal Title: Cell Rep. Volume: 29 Pages: 162-175
  • DOI: 10.1016/j.celrep.2019.08.086.
  • Peer Reviewed / Open Access
• [Presentation] Impaired development of myeloid cells in mice carrying a patient-derived proteasome subunit mutation. (2020)
  • Author(s): 邊見弘明、折茂貴是、佐々木泉、加藤喬、大田(福田)有里、金城紀子、濱田聡、木下晃、吉浦孝一郎、大西秀典、金澤伸雄、改正恒康
  • Organizer: 第3回日本免疫不全・自己炎症学会総会・学術集会
  • Invited
• [Presentation] Novel proteasome-related autoinflammation and immunodeficiency disease caused by a distinct heterozygous missense mutation in the PSMB9 gene. (2019)
  • Author(s): N. Kanazawa, Y. Nakatani, Y. Inaba, K. Kunimoto, N. Kinjo, S. Hamada, T. Mizushima, A. Kinoshita, K. Yoshiura, J. Hamazaki, S. Murata, H. Ohnishi, T. Orimo, H. Hemmi, T. Kaisho.
  • Organizer: The 44th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Invited
• [Presentation] 乳児期から発熱と凍瘡様皮疹を反復し、新規のインターフェロン調節遺伝子異常が疑われた親子例 (2019)
  • Author(s): 本田尭、土橋隆俊、番場正博、大方詩子、渡辺絵美子、宮川俊一、杉浦仁、稲葉豊、神人正寿、井澤和司、邊見弘明、改正恒康、三嶋博之、木下晃、吉浦孝一郎、金澤伸雄
  • Organizer: 第2回日本免疫不全・自己炎症学会総会・学術集会
  • Invited
• [Presentation] 複合免疫不全症を来す新規LIG4症候群モデルマウスは炎症性腸疾患を自然発症する (2019)
  • Author(s): 田村志宣、山下友佑、大田（福田）有里、小笹俊哉、金澤伸雄、安岡弘直, 邊見弘明, 大島孝一、改正恒康、園木孝志
  • Organizer: 第59回リンパ網内系学会
  • Invited
• [Presentation] コレラ毒素Bサブユニットは細胞内病原体センサーNLRP3とPyrinを介して炎症性サイトカインIL-1βの産生を誘導する (2019)
  • Author(s): 佐々木泉、折茂貴是、邊見弘明、古川鋼一、改正恒康
  • Organizer: 第29回日本樹状細胞研究会
  • Invited
• [Presentation] ヒト疾患由来プロテアソームサブユニット突然変異導入マウスにおける樹状細胞分化障害 (2019)
  • Author(s): 邊見弘明、小笹俊哉、加藤喬、折茂貴是、大田（福田）有里、金澤伸雄、改正恒康
  • Organizer: 第29回日本樹状細胞研究会
  • Invited
• [Presentation] Lig4遺伝子改変マウスを用いた腸管免疫寛容破綻の病態解明 (2019)
  • Author(s): 田村志宣、山下友佑、折茂貴是、大田（福田）有里、小笹俊哉、中嶋一貴、金澤伸雄、邊見弘明、大島孝一、改正恒康、園木孝志
  • Organizer: 第47回日本臨床免疫学会総会
  • Invited
• [Presentation] 実験的自己免疫性脳脊髄炎の病態形成における腸管免疫系の重要性の検証 (2019)
  • Author(s): 込山星河、江川愛子、高橋大輔、改正恒康、長谷耕二
  • Organizer: 日本薬学会関東支部会
  • Invited
• [Presentation] コレラ毒素Bサブユニットによる炎症性サイトカインIL-1β産生誘導機構 (2019)
  • Author(s): 佐々木泉、折茂貴是、邊見弘明、土屋慧馬、井上正一、熊谷直光、古川鋼一、改正恒康
  • Organizer: 第26回日本免疫毒性学会学術年会
  • Invited
• [Presentation] Akimichi Morita, Sayuri Yamazaki.Successful treatment of psoriatic inflammation improves hyperglycemia in humans and mice. (2019)
  • Author(s): M. Odanaka, K. Ikumi, H. Shime, M. Imai, E. Nishida, H. Hemmi, T. Kaisho.
  • Organizer: 第48回日本免疫学会総会・学術集会記録
  • Invited
• [Presentation] Defective dendritic cell and monocyte development in proteasome subunit mutant miceDefective dendritic cell and monocyte development in proteasome subunit mutant mice. (2019)
  • Author(s): H. Hemmi, T. Orimo, I. Sasaki, T. Kato, Y. Fukuda-Ohta, N. Kinjo, S. Hamada, A. Kinoshita, K. Yoshiura, H. Ohnishi, N. Kanazawa, T. Kaisho.
  • Organizer: 第48回日本免疫学会総会・学術集会記録
  • Invited
• [Presentation] Roles of endoplasmic reticulum stress in cholera toxinB-induced interleukine-1β production from resident peritoneal macrophages. (2019)
  • Author(s): I. Sasaki, S. Morita, D. Okuzaki, T. Orimo, H. Hemmi, K. Furukawa, T. Kaisho.
  • Organizer: 第48回日本免疫学会総会・学術集会記録
  • Invited
• [Presentation] Novel proteasome-related autoinflammation and immunodeficiency disease caused by a distinct heterozygous missense mutation in the PSMB9 gene. (2019)
  • Author(s): N. Kanazawa, N. Kinjo, S. Hamada, T. Mizushima, A. Kinoshita, K. Yoshiura, J. Hamazaki, S. Murata, H. Ohnishi, T. Orimo, H. Hemmi, T. Kaisho.
  • Organizer: 第48回日本免疫学会総会・学術集会記録
  • Invited
• [Presentation] Generation and analysis of mice carrying a novel heterozygous missense mutation of a protease subunit, PSMB9, in patients with autoinflammation and immunodeficiency. (2019)
  • Author(s): H. Hemmi, N. Kanazawa, N. Kinjo, S. Hamada, H. Ohnishi, T. Mizushima, A. Kinoshita, K.-I. Yoshiura, T. Kaisho.
  • Organizer: The 10th Biannual Meeting of the International Society of Systemic Auto-Inflammatory Diseases (ISSAID)
  • Int'l Joint Research
• [Presentation] A case of neonatal-onset proteasome-associated autoinflammation and immunodeficiency disease resembling but distinct from Nakajo-Nishimura syndrome. (2019)
  • Author(s): Kinjo, S. Hamads, K. Nakanishi, H. Mishima, A. Kinoshita, K.-I. Yoshiura, T. Mizushima, J. Hamazaki, S. Murata, H. Hemmi, T. Kaisho, N. Kanazawa.
  • Organizer: The 10th Biannual Meeting of the International Society of Systemic Auto-Inflammatory Diseases
  • Int'l Joint Research
• [Presentation] Regulatory T cells with a distinctive feature expand through dermal dendritic cells in the ultraviolet B exposed skin. (2019)
  • Author(s): S. Yamazaki, M. Odanaka, H. Shime, M. Imai, H. Hemmi, T. Kaisho, N. Ohkura, S. Sakaguchi, A. Morita.
  • Organizer: 16th International Workshop on Langerhans Cells
  • Int'l Joint Research
• [Presentation] Sox8 is essential for the maturation of M cells and accelerates IgA response at the early stage after weaning. The 18th Awaji International Forum on Infection and Immunity. (2019)
  • Author(s): N. Kobayashi, S. Kimura, Y. Nakamura, T. Kanaya, T. Kaisho, H. Ohno, T. Iwanaga, K. Hase.
  • Organizer: Awaji Yumebutai International Conference Center
  • Int'l Joint Research
• [Presentation] Cholera toxin B can induce interleukine-1β production from resident peritoneal macrophages in synergy with lipopolysaccharides. (2019)
  • Author(s): I. Sasaki, T. Orimo, H. Hemmi, K. Furukawa, T. Kaisho.
  • Organizer: The 18th Awaji International Forum on Infection and Immunity.
  • Int'l Joint Research
• [Presentation] ケモカイン受容体XCR1を発現する樹状細胞サブセットによる免疫制御 (2019)
  • Author(s): 改正恒康.
  • Organizer: 近畿大学薬学部
  • Invited
• [Remarks] 新規抗がんワクチン開発 県立医大が成果を発表
  • URL: https://www.wakayamashimpo.co.jp/2020/03/20200317_92750.html
• [Remarks] 県立医科大研究チームが新がんワクチン開発
  • URL: https://www.hidakashimpo.co.jp/news1/2020/03
• [Remarks] 抗がん活性の強い樹状細胞へがん抗原ペプチドを選択的に送達させる新規抗がんワクチンの開発
  • URL: https://research-er.jp/articles/view/87282